Associations between smoking and alcohol consumption with blood pressure in a middle-aged population

INTRODUCTION Inconsistent association between tobacco smoking, alcohol consumption and hypertension have been highlighted. The purpose of our study was to investigate the associations between smoking use and alcohol with systolic and diastolic blood pressure (SBP, DBP) and hypertension in a middle-aged population. METHODS Smoking status was based on smoking pack-years and cigarettes per day, and alcohol consumption was measured in units/day. Gender associations between smoking and alcohol consumption with BP and hypertension were estimated using multiple linear regressions. Synergistic effects between smoking and alcohol were investigating in both genders. RESULTS A total of 290913 individuals of the UK Biobank population were included (133950 men and 156963 women). Current smoking was significantly associated with lower SBP, DBP and lower hypertension prevalence, in both genders (p<0.001). However, cigarettes per day were associated with higher SBP in men current smokers [B=0.05 (0.02), p<0.001] with higher hypertension (p=0.001) but not with DBP (p=0.205). Similar results were observed in women current smokers [SBP: B=0.10 (0.02), p<0.001; DBP, p=0.217 and hypertension, p=0.019]. The number of smoking pack-years was only associated with higher levels in SBP in men (p=0.047) and in women (p<0.001). In both genders, alcohol consumption was associated with higher SBP, DBP and hypertension (p<0.001). Synergistic effects were observed for alcohol consumption on smoking pack-years and cigarettes per day with SBP and DBP. CONCLUSIONS Smoking and alcohol were associated with higher BP in current smokers with synergistic effects. The findings suggest the importance of considering smoking and alcohol consumption in BP control in addition to antihypertensive medication and public health practice.


INTRODUCTION
Hypertension (HTN) was the main risk factor for global burden and accounted for more than 9 million deaths in 2010 1 . In parallel, tobacco smoking is one of the major public health challenge and was responsible for more than 6 million deaths per year worldwide 1 . The relation between blood pressure (BP) and tobacco habits remained unclear among studies showing a positive 2 or a negative association 3 . The association between tobacco smoking and low BP could be explained by different behaviors or socioeconomic factors 4 . Current smokers may have a lower body mass index (BMI) than non-smokers, which could explain this negative association 5 .
Nevertheless, other epidemiological studies showed that smoking tobacco was associated with high BP 6 . The combination of tobacco smoking and high BP may have a synergistic effect on cardiovascular events 7 . However, few studies have focused on smoking impact on BP levels in current smokers.
In parallel, recent guidelines recommended to limit daily alcohol consumption to two or fewer drinks per day for men and one drink for women 8 . A positive association between heavy drinking and hypertension has been found 9 ; however, this relationship remains unclear, especially in women.
Many people both smoke and drink, and many chemical pathways should reinforce this association 10 . The combination of smoking and alcohol intake is associated with increased risk of mortality 11 . Patterns of both drinking and smoking are highly socially associated, even if health public policies fight these unhealthy behaviors. Few studies have focused on these combinations on hypertension and BP in the general population. Thus, the purpose of this study was to investigate the associations between tobacco smoking and alcohol consumption with BP and hypertension, and their combinations, in a middleaged population.

UK Biobank population
The UK Biobank is a prospective cohort for the investigation, prevention, diagnosis, and treatment of chronic diseases, such as cardiovascular (CV) diseases in adults. A total of 502478 Britons from the UK National Health Service Register were included between 2006 and 2010, across 22 UK cities. The cohort was phenotyped and genotyped from participants who responded to a questionnaire and had a computer-assisted interview, from their physical and functional measures, and who provided blood, urine, and saliva samples. Data included socioeconomic, behavior and lifestyle, mental health battery, clinical diagnoses and therapies, genetics, imaging, and physiological biomarkers from blood and urine samples. The cohort protocol can be found in the literature 12 .

Study population
In all, 499549 volunteers of the UK Biobank who responded to the questionnaire on smoking status were recruited. We excluded 28990 participants with previous CV events from the analyses due to the interaction between tobacco smoking and CV disorders; 179646 participants were excluded for missing data, and we thus analyzed 290913 individuals in this study ( Figure 1). Systolic (SBP) and diastolic blood pressure (DBP) were measured twice at the assessment center by the use of an automated BP device (

Covariates
Diabetes status was defined on either receiving anti-diabetic medication or diabetes diagnosed by a doctor or a fasting glucose concentration ≥7mmol/L. Dyslipidemia was defined as having a fasting plasma total-cholesterol or triglycerides level of ≥6.61 mmol/L (255 mg/dL) or >1.7 mmol/L (150 mg/dL), respectively, or having statins medication. Medications were characterized by the question: 'Do you regularly take any of the following medications?'.
Hypertension was defined as SBP of at least 140 mmHg and/or DBP of at least 90 mmHg, according to guidelines by the European Society of Cardiology, and/or antihypertensive drug used, or hypertension diagnosed by a doctor. CV diseases were defined by heart attack, angina, and stroke, as diagnosed by a doctor, and reported in questionnaires. Body mass index (BMI) was calculated as weight (kg) divided by height-squared (m 2 ) and categorized as: high >30, moderate 25-30, and low <25 kg/m 2 ). Biological parameters were detailed in the UK Biobank protocol. Education level was defined in three categories: high (college or university degree); intermediate (A/AS levels or equivalent, O levels/GCSEs or equivalent, other profession qualification, e.g. nursing, teaching etc.); and low (none of the aforementioned). Yearly income level (in £) was defined as: high, >52000; moderate, 18000-51999; and low, <18000.

Smoking status
Participants were categorized by self-report, as 'current', 'past' or 'never' smokers. Current tobacco smokers were defined as participants who responded 'yes, on most or all days' or 'yes, only occasionally' to the question: 'Do you smoke tobacco now?'. Smoking pack-years were calculated for individuals who have ever smoked. Smoking pack-years were calculated as the average number of packs smoked per day multiplied by the total number of years of smoking in lifetime. The general definition of a pack-year is the number of cigarettes smoked per day, divided by twenty, multiplied by the number of years of smoking. In the UK Biobank, the number of years of smoking is calculated by subtracting the age of starting smoking from the age smoking was stopped (or age at inclusion for current smokers), using the equation: Pack-years = Number of cigarettes per day/20×(age stopped smoking -age started smoking) For current smokers, the participants had to respond to: 'About how many cigarettes do you smoke on average per day?'; and for past smokers: 'About how many cigarettes did you smoke on average per day?'. Participants who responded 'never smoked' were allocated zero for both smoking pack-years and cigarettes per day.

Alcohol consumption
Although the alcohol questionnaire has not been formally validated, several studies have shown expected associations with alcohol 15

Statistical analysis
Characteristics of the study population were described as mean with standard deviation (SD) for continuous variables. Categorical variables were described as number and percentage. Statistical analyses were stratified by gender since hypertension differs between men and women 16 and a difference in tobacco consumption between gender was observed 17 . Comparisons between all groups of smoking status were performed using ANOVA tests.
Association between smoking status, smoking pack-years or cigarettes per day with alcohol status or alcohol consumption per day, and blood pressure levels (SBP and DBP), were examined with linear regression models, computing regression coefficients (B) with standard error (SE), adjusted for Model 1: antihypertensive medication + age; Model 2: model 1 + BMI; and Model 3: model 2 + diabetes, dyslipidemia, education level, and income level.
Associations between smoking status and alcohol consumption with hypertension prevalence were examined with logistic regression models with odds ratio (OR) and 95% confidence interval (CI), adjusted for Model 1: antihypertensive medication + age; Model 2: model 1 + BMI; and Model 3: model 2 + diabetes, dyslipidemia, education level and income level. Interactions were examined by including simultaneous alcohol consumption per day and smoking pack-years or cigarettes per day and their interaction term. Relationships between smoking and alcohol consumption with SBP, DBP, and hypertension were investigated in each subgroup, i.e. current, past, or never smokers. To investigate the synergistic effects between smoking pack-years/cigarettes per day and alcohol consumption on blood pressure (SBP and DBP) in current smokers, the differences in correlation were assessed using Steiger's Z test between the adjusted individuals and combined models. Statistics were performed using SAS software (version 9.4; SAS Institute, Carry, NC). A p<0.05 was considered statistically significant.
In the men population, smoking pack-years was negatively and significantly associated with SBP     Table 3).
Significant interactions were observed between smoking status and alcohol status in both genders (men, p<0.001; and women, p=0.075), smoking pack-years and alcohol consumption per day (men, p=0.022; and women, p<0.001), and between cigarettes per day and alcohol consumption per day (men, p=0.007; and women, p<0.001).
Among men current smokers, a significant association was observed between SBP and smoking pack-years [Model 3: B=0.01 (0.001), p=0.047] but not with DBP (p=0.054) and hypertension prevalence (p=0.248) ( Table 4). Similar results were observed between cigarettes per day with SBP (p=0.001) and DBP (p=0.205), but showing a significant association with hypertension (Model 3: OR=1.01; 95% CI: 1.00-1.02, p<0.001). SBP and DBP, adjusted for Model 3, showed linear significant correlations with both smoking packyears (p<0.001) and cigarettes per day (p<0.001) among current men and women smokers (Figure 2). Men current smokers with >30 smoking pack-years showed higher proportion of hypertension ( Figure 3). Similar results were observed between adjusted SBP

Figure 2. Linear regressions between SBP and DBP with smoking pack-years and cigarettes per day in men and women current smokers
SBP and DBP were adjusted for Model 3: antihypertensive medication, age, BMI, diabetes, dyslipidemia, education level, and income level. SBP: systolic blood pressure. DBP: diastolic blood pressure. and DBP with cigarettes per day ( Figure 3). Among women current smokers, a significant association was observed between SBP and smoking pack-years [Model 3: B=0.04 (0.01), p<0.001] but not with DBP (p=0.188) and hypertension prevalence (p=0.176) ( Table 4). Similar results were observed between cigarettes per day with SBP (p<0.001) and DBP (p=0.217), but showing a significant association with hypertension (p=0.019). SBP and DBP, adjusted for Model 3, showed linear significant correlations with both smoking pack-years (p<0.001) and cigarettes per day (p<0.001) among women current smokers ( Figure  2). Women who consumed >30 smoking pack-years showed higher proportion of hypertension (Figure 3). Similar results were observed between adjusted SBP and DBP with cigarettes per day (Figure 3).
For hypertension determination, among current smokers, logistic regressions were performed, and a threshold at 12 cigarettes per day was observed in women (p<0.001) and 11 cigarettes per day in men (p<0.001). Alcohol consumption per day was significantly associated with SBP, DBP and hypertension in all subgroups of current, past, and never smokers (Table 4). For hypertension determination, among current smokers, logistic regressions were performed, and a threshold at 2.71 units per day was observed in women (p<0.001) and 3.19 units per day in men (p<0.001).  Figure 3. Hypertension prevalence among men and women current smokers according to: A) subgroups of number smoking pack-years, and B) subgroups of number cigarettes per day Added values in models were observed when including alcohol consumption in models for smoking information, i.e. p<0.001 for smoking pack-years and p<0.001 for cigarettes per day in both genders and for both SBP and DBP (Table 5). However, no added values were observed when including smoking information in models of alcohol consumption (men: SBP, p=0.630 and for DBP, p=0.589; women: for SBP, p=0.619 and for DBP, p=0.921).

DISCUSSION
This study investigated the association between smoking and alcohol consumption with blood pressure according to gender. The findings revealed that SBP and DBP were lower among current smokers than never smokers in both genders and after adjustment for all covariates. Alcohol consumption was significantly and positively associated with higher levels of SBP, DBP and hypertension in men and women. We observed an interaction between smoking and alcohol status in both men and women. We found in current smokers a positive association between smoking pack-years and cigarettes per day with SBP in both genders, but not with DBP, and only for cigarettes per day with hypertension prevalence in both men and women. Synergistic effects were observed by adding alcohol consumption on smoking models in men and women.

Tobacco smoking and hypertension
Several social factors and individual behaviors can display BP levels among current smokers 18 . However, studies have reported that smoking increases BP 6 . High level of nicotine activates the sympathetic nervous system leading to a release of epinephrine, norepinephrine and vasopressin hormones 19 . Nevertheless, the chronic effect of tobacco smoking remains unclear. Several studies showed that current smokers had lower BP levels compared to non-smokers 3 . However, epidemiological studies showed a dose-dependent effect of smoking on BP 2,6 , even if a meta-analysis highlighted no causal association between BP and smoking heaviness in current smokers 4 . Moreover, former smokers were higher hypertensive than never smokers and the risk of hypertension increased with the number and duration of cigarettes smoked 20 . Nevertheless, there is no consensus regarding the role of chronic tobacco smoking on BP. Tobacco smoking has chemical toxicants which can have detrimental effects and damage 18 . Some findings showed that chronic smokers presented high BP values 21 . More so, since chronic smokers had higher SBP than those hypertensive because of old age 22 . Chronic smoking enhanced several pathways such as oxidative stress, alteration of nitric oxide (NO) and bioavailability, endothelial dysfunction, and then increased BP 7,20 . The effect of

Alcohol and hypertension
Consistent with previous studies, our findings highlight that alcohol consumption is significantly associated with increased BP 26 . However, the association between hypertension and alcohol consumption remains unclear in women 27 . A metaanalysis study assessed the presence of a genderspecific relationship between alcohol consumption and hypertension 9 . In our study, we found different thresholds for alcohol consumption and hypertension determination: 3.19 units/day for men, and 2.71 units/day for women. These findings are consistent with a recent meta-analysis showing that alcohol consumption increased the risk of hypertension in men for consumption of more than 1 to 2 drinks/ day (when considering one red wine drink=2 units) while heavy consumptions were significant in both genders 28 . Thus, a gender dose-response relationship was observed between alcohol consumption and hypertension. One of the possible explanations could be the many drinking occasions with an average of alcohol consumption among men than women ( Table  1). The frequency of alcohol consumption presented different effects on BP 29 . Previous studies have shown that the consumption amount of alcohol was associated with high BP and that the reduction in alcohol intake lowered BP in a dose-dependent response 6 . Alcohol consumption may be responsible for vasoconstriction of blood vessels, increased heart rate, activation of the sympathetic nervous system and loss in magnesium 6 .

Synergistic effects of tobacco smoking and alcohol consumption on hypertension
Drinking and smoking behaviors generally occur together 30 . Alcohol consumption can affect the relationship between smoking and BP, whereas the relationship between alcohol consumption and BP did vary by smoking status 31 . Thus, the synergistic effects remained unclear. The fact that both alcohol consumption and tobacco smoking can interact with the sympathetic nervous system could explain a synergistic effect. However, only one study has shown that the combine reduction in alcohol consumption and tobacco smoking was associated with reduction in hypertension 32 . Moreover, very few studies have focused on this possible interaction to highlight this possible synergistic effect among current smokers 6,31 .
Our study showed an added effect of alcohol consumption on smoking pack-years and cigarettes per day in current smokers. The alcohol consumption effect could be reinforced by the neurochemical action of nicotine, explaining the added value of alcohol in smokers 33 . However, we found no added effect of tobacco consumption on alcohol consumption. Alcohol is known to be highly associated with abdominal obesity and thus increased risk of obesity 34 whereas tobacco smoking was correlated with lower BMI 35 . As BMI, after age, was one of the main factors of increased risk of hypertension 36 , the absence of added effects of tobacco use on alcohol consumption observed could be explained by these inverse interactions with BMI.

Strengths and limitations
The main strength of this study is the very large sample size of the cohort. The cross-sectional observational design limits the relationship of causality. Reverse causation cannot be ruled out. The UK Biobank study showed a low response rate of 5.5% and possible volunteers bias may be involved. Nevertheless, given the large sample size and high internal validity, these are unlikely to affect the reported associations. In addition, the study cohort consisted of middleaged European participants, so our findings may not be generalized to other age groups and ethnic populations. In addition, the UK Biobank used standardized protocols to collect anthropometric data including BP measurements; this ensures replication of data collection for all volunteers regardless of when, where and by whom they are performed and adds validity to our results. However, our study presents some limitations. Socioeconomic data were collected by self-reporting. Medical history and comorbidities have been collected by self-reporting and physician verification during medical examination in health centers. The cross-sectional design of the study may represent a limitation since reverse causation cannot be excluded. Smoking pack-years, cigarettes per day and alcohol consumption were self-reported by questionnaire. Moreover, periods of quitting smoking have not been included in calculating smoking packyears, due to a lack of information about the duration period of stop smoking. Due to the adjustment for several factors which are causal pathways, a collider bias should be considered for the interpretation of the results observed.

CONCLUSIONS
Our findings showed lower BP in current smokers than never smokers in both genders. Nevertheless, among current smokers smoking pack-years, cigarettes per day and alcohol consumption were associated with higher BP. Synergistic effects of alcohol consumption on tobacco smoking were observed for SBP and DBP. Although the relationships remained modest, these risk factors could be considering to be part of the public health policies to reduce hypertension risk.